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Cited by 649Mosquito-borne diseases and controlInsect symbiosis and bacterial influencesDengue and Mosquito Control Research

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Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue

Open access
Utarini, Adi, Indriani, Citra, Ahmad, Riris A., Tantowijoyo, Warsito, Arguni, Eggi, Ansari, M. Ridwan, Supriyati, Endah, Wardana, D. Satria, Meitika, Yeti, Ernesia, Inggrid, Nurhayati, Indah, Prabowo, Equatori, Andari, Bekti, Green, Benjamin R., Hodgson, Lauren, Cutcher, Zoe, Rancès, Edwige, Ryan, Peter A., O’Neill, Scott L., Dufault, Suzanne M., Tanamas, Stephanie K., Jewell, Nicholas P., Anders, Katherine L., Simmons, Cameron P.·2021·New England Journal of Medicine
DOI 10.1056/nejmoa2030243PMC PMC8103655
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Abstract

BACKGROUNDAedes aegypti mosquitoes infected with the wMel strain of Wolbachia pipientis are less susceptible than wild-type A. aegypti to dengue virus infection. METHODSWe conducted a cluster-randomized trial involving releases of wMel-infected A. aegypti mosquitoes for the control of dengue in Yogyakarta, Indonesia.We randomly assigned 12 geographic clusters to receive deployments of wMel-infected A. aegypti (intervention clusters) and 12 clusters to receive no deployments (control clusters).All clusters practiced local mosquito-control measures as usual.A testnegative design was used to assess the efficacy of the intervention.Patients with acute undifferentiated fever who presented to local primary care clinics and were 3 to 45 years of age were recruited.Laboratory testing was used to identify participants who had virologically confirmed dengue (VCD) and those who were testnegative controls.The primary end point was symptomatic VCD of any severity caused by any dengue virus serotype. RESULTSAfter successful introgression of wMel into the intervention clusters, 8144 participants were enrolled; 3721 lived in intervention clusters, and 4423 lived in control clusters.In the intention-to-treat analysis, VCD occurred in 67 of 2905 participants (2.3%) in the intervention clusters and in 318 of 3401 (9.4%) in the control clusters (aggregate odds ratio for VCD, 0.23; 95% confidence interval [CI], 0.15 to 0.35; P = 0.004).The protective efficacy of the intervention was 77.1% (95% CI, 65.3 to 84.9) and was similar against the four dengue virus serotypes.The incidence of hospitalization for VCD was lower among participants who lived in intervention clusters (13 of 2905 participants [0.4%]) than among those who lived in control clusters (102 of 3401 [3.0%]) (protective efficacy, 86.2%; 95% CI, 66.2 to 94.3). CONCLUSIONSIntrogression of wMel into A. aegypti populations was effective in reducing the incidence of symptomatic dengue and resulted in fewer hospitalizations for dengue among the participants.(Funded by the Tahija Foundation and others; AWED ClinicalTrials.govnumber, NCT03055585; Indonesia Registry number, INA-A7OB6TW.)

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Crossref · 10.1056/nejmoa2030243

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Figures

Figure 1: Map of study location. In panel A, the map of Indonesia is shown with the Special Region of Yogyakarta shaded blue. In panel B, the map of Yogyakarta City (plus a small region of neighbouring Bantul District) is shown with wMel intervention clusters (shaded blue) and untreated clusters (shaded grey) indicated. The locations of primary care clinics (red crosses) where enrolment occurred are also shown.
Figure 1: Map of study location. In panel A, the map of Indonesia is shown with the Special Region of Yogyakarta shaded blue. In panel B, the map of Yogyakarta City (plus a small region of neighbouring Bantul District) is shown with wMel intervention clusters (shaded blue) and untreated clusters (shaded grey) indicated. The locations of primary care clinics (red crosses) where enrolment occurred are also shown.CC BY · PubMed Central
Figure 2: wMel introgression into local Aedes aegypti mosquito populations. Lines show the percentage of Ae. aegypti collected from intervention clusters (A) and untreated clusters (B) that were wMel infected, each month from the start of deployments (March 2017) to the end of participant enrolment (March 2020). The shaded area indicates the period from the first release in the first cluster (March 2017) to the last release in the last cluster (December 2017). There were between 9 and 14 fortnightly release rounds per cluster.
Figure 2: wMel introgression into local Aedes aegypti mosquito populations. Lines show the percentage of Ae. aegypti collected from intervention clusters (A) and untreated clusters (B) that were wMel infected, each month from the start of deployments (March 2017) to the end of participant enrolment (March 2020). The shaded area indicates the period from the first release in the first cluster (March 2017) to the last release in the last cluster (December 2017). There were between 9 and 14 fortnightly release rounds per cluster.CC BY · PubMed Central
Figure 3: Cluster randomisation, participant enrolment, inclusion in analysis dataset, and follow-up of safety endpoints. The commonest reasons for exclusion from the analysis dataset were enrolment before the predefined time point of Wolbachia establishment (8th January 2018), enrolment in a calendar month without any VCD cases (September 2018) or having positive or equivocal dengue IgM or IgG serology at enrolment that precluded classification as a test-negative control.
Figure 3: Cluster randomisation, participant enrolment, inclusion in analysis dataset, and follow-up of safety endpoints. The commonest reasons for exclusion from the analysis dataset were enrolment before the predefined time point of Wolbachia establishment (8th January 2018), enrolment in a calendar month without any VCD cases (September 2018) or having positive or equivocal dengue IgM or IgG serology at enrolment that precluded classification as a test-negative control.CC BY · PubMed Central
Figure 4: Intention-to-treat efficacy. Shown is the protective efficacy (expressed as 100×(1−OR)) of wMel-infected Aedes aegypti deployments against virologically-confirmed dengue of any serotype (All VCDs), by infecting DENV serotype, and against hospitalised VCD. VCDs with ‘Unknown serotype’ were test-negative by DENV RT-PCR and test-positive for DENV NS1 antigen. Seven participants had two DENV serotypes detected during the same febrile episode: four with serotypes 1 and 2, two with serotypes 1 and 4, and one with serotypes 2 and 4.
Figure 4: Intention-to-treat efficacy. Shown is the protective efficacy (expressed as 100×(1−OR)) of wMel-infected Aedes aegypti deployments against virologically-confirmed dengue of any serotype (All VCDs), by infecting DENV serotype, and against hospitalised VCD. VCDs with ‘Unknown serotype’ were test-negative by DENV RT-PCR and test-positive for DENV NS1 antigen. Seven participants had two DENV serotypes detected during the same febrile episode: four with serotypes 1 and 2, two with serotypes 1 and 4, and one with serotypes 2 and 4.CC BY · PubMed Central
Figure 5: Cluster-level proportions of virologically-confirmed dengue cases. VCD cases as a proportion of all participants in Wolbachia-treated (closed circles) and untreated (open circles) clusters. Circle size is proportionate to the total number of participants in the cluster. Circles are labelled with their respective cluster number. Horizontal bars show the mean VCD proportion in intervention and untreated clusters; the relative risk and P-value are derived from a comparison of these mean proportions (see Methods).
Figure 5: Cluster-level proportions of virologically-confirmed dengue cases. VCD cases as a proportion of all participants in Wolbachia-treated (closed circles) and untreated (open circles) clusters. Circle size is proportionate to the total number of participants in the cluster. Circles are labelled with their respective cluster number. Horizontal bars show the mean VCD proportion in intervention and untreated clusters; the relative risk and P-value are derived from a comparison of these mean proportions (see Methods).CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Department of Control of Neglected Tropical Diseases, Special Programme for Research and Training in Tropical Diseases. Dengue: guidelines for diagnosis, treatment, prevention and control. Geneva: World Health Organization, 2009.

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Metadata

Authors
Utarini, A., Indriani, C., Ahmad, R. A., Tantowijoyo, W., Arguni, E., Ansari, M. R., Supriyati, E., Wardana, D. S., Meitika, Y., Ernesia, I., Nurhayati, I., Prabowo, E., Andari, B., Green, B. R., Hodgson, L., Cutcher, Z., Rancès, E., Ryan, P. A., O’Neill, S. L., Dufault, S. M., Tanamas, S. K., Jewell, N. P., Anders, K. L., & Simmons, C. P.
Affiliations
Universitas Gadjah Mada (ID)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2021-06-10
Volume
384
Issue
23
Pages
2177-2186
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa2030243
PMC
PMC8103655
OpenAlex
W3172070999
Cited by
649
References
33
Citations by year
2026: 121 · 2025: 143 · 2024: 127 · 2023: 121 · 2022: 96 · 2021: 40
FWCI
84.34
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • New England Journal of Medicine (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
Funders
  • Wellcome Trust (212914)
  • National Institute of Allergy and Infectious Diseases (R01AI148127)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
  • Life Sciences › Agricultural and Biological Sciences › Insect Science › Insect symbiosis and bacterial influences
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Dengue and Mosquito Control Research
Keywords
Wolbachia, wMel strain, Aedes aegypti, dengue control, mosquito release, dengue virus, test-negative design, protective efficacy, dengue hospitalization, mosquito control, Yogyakarta, dengue serotypes, dengue surveillance, dengue prevention
MeSH terms
Mosquito Vectors, Adolescent, Adult, Aedes, Animals, Child, Child, Preschool, Communicable Disease Control, Dengue, Dengue Virus, Female, Humans, Indonesia, Male, Middle Aged, Incidence, Wolbachia, Young Adult

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